The overall objective of this project is to further the value of the mouse as a powerful and important tool in the study of human disease through the establishment of a publicly available, comprehensive collection of a fully C57BU6-based null resource knockout embryonic stem cell lines, from which ajibrary of mice containing a null mutation in every gene in the mouse genome can be developed. This application proposes to establish an international consortium of academic institutions comprised of four Canadian (Drs. Naqy. Hicks. Ding and Rancourt). one German (Dr. Wurst) laboratories and the University of Missouri Comparative Medicine Center (Dr. Critser). This consortium was developed to address the NIH RFA (RFA-HG-05-007)for the production of a comprehensive resource of mouse mutants in which every gene in the mouse genome has been knocked out by a null mutation marked with a reporter system of high utility. This consortium fulfills the criteria for an ideal resource in that all of the mutations will be carried on a uniform background strain, C57BL/6, which is the strain most widely utilized by mouse researchers. The unique aspect of this overall proposal is that one laboratory in the consortium (Dr. Nagy's laboratory) has established an exceptional C57BL/6 embryonic stem cell line with a very high germline transmission (-70%). Importantly, this consortium has members which are also part of a Canadian funded project (NORCOMM; Nagy, Hicks, Ding and Rancourt labs) and a European Union funded project (EUCOMM; Wurst lab) to perform high throughput gene mutations in embryonic stems cells. Combining the existing experience and expertise of three major laboratories making null mutations, in combination with the Nagy lab's high germline efficient C57BL/6 embryonic stem cell line and the University of Missouri's expertise in creation of mice and operation of quality control/assurance programs for large NIH-funded resources; will provide a highly efficient and cost effective 'learn" to achieve the goals of this RFA. While several consortium members are involved with similar world-wide efforts to provide a complete library of mouse null imitations, there is no overlap between those projects and this KOMP initiative. In fact, a major strength of this proposal is the vast experience and existing infrastructure in those laboratories. The existing high throughput, low cost methods that are "up and running" in our collective laboratories enable this consortium to accomplish the goals of the KOMP an extremely timely and cost efficient manner. Importantly, because this consortium is comprised of academic groups, in which there are multiple, separately funded, ongoing research projects directly related to the KOMP, we will be able to ensure continuous access to, and application of, the most cutting-edge technologies and science; thereby providing continuous quality improvement over the course of this KOMP. This aspect will ensure the most cost effective methods are applied at each step along the way to completing the core goals of the KOMP.